(1) Field of the Invention
The present invention generally relates to cancer treatments. More specifically, the invention is directed to methods of inhibiting the Skp2-cyclin A interaction.
(2) Description of the Related Art
Skp2 is one of the founding members of the F-box protein family that serves as the ubiquitylation substrate recruiting subunit of the SCFSkp2Roc1 complex (Bai et al., 1996). The best-established substrate of Skp2 is the CKI p27 (Carrano et al., 1999; Sutterluty et al., 1999; Tsvetkov et al., 1999), although Skp2 can also promote ubiquitylation and degradation of other proteins including the p27 family members p21 (Bornstein et al., 2003) and p57 (Kamura et al., 2003). Since p27 is a negative regulator of cell proliferation, the p27 ubiquitylation activity of Skp2 suggested that it is a proliferation-stimulating protein. Indeed, Skp2 exhibits proliferation-stimulating activity in various experimental assays and is found overexpressed in various human cancers (Nakayama and Nakayama, 2005).
Another property of Skp2 is its interaction with cyclin A. In fact, Skp2 was first identified and cloned as a cyclin A associated protein in transformed cells (Xiong et al., 1993), and Skp2 associated with both cyclin A and Skp1 in stoichiometric amounts (Zhang et al., 1995). If protein-protein interactions and the efficiencies of interactions are indications to protein functions, these early findings should suggest that Skp2-cyclin A interaction is an important aspect of Skp2 function. Surprisingly however, prior to the present work, very little has been learned about the Skp2-cyclin A interaction more than ten years after its identification. Mapping of cyclin A interacting sequences of Skp2 was uncertain and the functional significance of Skp2-cyclin A interaction was controversial (see below). The role of Skp2 as a proliferation-stimulating protein has been exclusively attributed to p27 ubiquitylation and degradation.